Continuous-flow quaternization reaction of gramines with MeI (&lt; 1 min) followed by substitution reaction with a chiral nucleophilic glycine-derived Ni-complex (&lt; 1 min) has successfully been developed to afford the corresponding alkylated Ni-complexes in good yield with excellent diastereoselectivity, based on the results of one-pot quaternization-substitution reaction of gramines with the chiral Ni-complex in batch process. The continuous-flow process allowed safe and efficient scale-up synthesis of an alkylated Ni-complex (84% yield, 99% de, 540 g/h) from 7-azagramine to give 7-azatryptophan derivative readily by acid catalyzed hydrolysis reaction followed by protection with an Fmoc group. The present method for rapid and efficient syntheses of enantiopure unnatural tryptophan derivatives from various gramines and the chiral Ni-complex<b> </b>will be useful to further promote peptide and protein drug discovery and development research.

Rapid and efficient syntheses of tryptophans using continuous-flow quaternization-substitution reaction of gramines with a chiral nucleophilic glycine equivalent

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